Cross-tissue transcriptome-wide association studies identify susceptibility genes shared between schizophrenia and inflammatory bowel disease

Uellendahl-Werth, Florian; Maj, Carlo; Borisov, Oleg; Juzėnas, Simonas; Wacker, Eike Matthias; Jørgensen, Isabella Friis; Steiert, Tim Alexander; Bej, Saptarshi; Krawitz, Peter; Hoffmann, Per; Schramm, Christoph; Banasik, Karina; Brunak, Søren; Schreiber, Stefan; Karlsen, Tom H.; Degenhardt, Franziska; Nöthen, Markus M.; Franke, André; Folseraas, Trine; Ellinghaus, David

doi:10.1038/s42003-022-03031-6

Cited by 19 publications

(24 citation statements)

References 81 publications

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“…It included 116,164 patients with schizophrenia and 464,656 matched controls and concluded that overall incidence of IBD was significantly higher amongst the schizophrenia cohort (1.14% vs 0.25%); risk was also higher amongst those with more severe schizophrenia. These findings are potentially supportive of research suggestive of shared genetic susceptibility between the two conditions[ 84 , 85 ], although the role of diet and microbiota remain important confounding factors.…”

Section: Lower Gastrointestinal Diseasesupporting

confidence: 75%

Gastrointestinal and liver disease in patients with schizophrenia: A narrative review

Grant¹,

Brindle²,

Donnelly³

et al. 2022

World J Gastroenterol

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Schizophrenia is a severe mental illness which can have a devastating impact on an individual’s quality of life. Comorbidities are high amongst patients and life expectancy is approximately 15 years less than the general population. Despite the well-known increased mortality, little is known about the impact of gastrointestinal and liver disease on patients with schizophrenia. We aimed to review the literature and to make recommendations regarding future care. Literature searches were performed on PubMed to identify studies related to gastrointestinal and liver disease in patients with schizophrenia. High rates of chronic liver disease were reported, with Non-Alcoholic Fatty Liver Disease being of particular concern; antipsychotics and metabolic syndrome were contributing factors. Rates of acute liver failure were low but have been associated with antipsychotic use and paracetamol overdose. Coeliac disease has historically been linked to schizophrenia; however, recent research suggests that a causal link is yet to be proven. Evidence is emerging regarding the relationships between schizophrenia and peptic ulcer disease, inflammatory bowel disease and irritable bowel syndrome; clinical vigilance regarding these conditions should be high. Patients with schizophrenia poorly engage with bowel cancer screening programmes, leading to late diagnosis and increased mortality. Clozapine induced constipation is a significant issue for many patients and requires close monitoring. There is a significant burden of gastrointestinal and liver disease amongst patients with schizophrenia. Better levels of support from all members of the medical team are essential to ensure that appropriate, timely care is provided.

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Section: Lower Gastrointestinal Diseasesupporting

confidence: 75%

Gastrointestinal and liver disease in patients with schizophrenia: A narrative review

Grant¹,

Brindle²,

Donnelly³

et al. 2022

World J Gastroenterol

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“…A recent study provided new evidence that linked schizophrenia and epithelial EECs [ 73 ]. Uellendahl-Werth et al reported the susceptibility genes shared between EECs and schizophrenia.…”

Section: Enteroendocrine Cells In Schizophreniamentioning

confidence: 99%

“…Their results indicated that protein phosphatase 3 catalytic subunit alpha (PPP3CA) is the shared susceptibility locus for IBD (Crohn’s disease and ulcerative colitis) and schizophrenia. The genes were expressed in restricted tissues, including neurons in the brain, intestinal epithelial EECs, and Paneth cells in the ileum, colon, and rectum [ 73 ]. The authors also provided two possible mechanisms by which PPP3CA in EECs contributes to disease pathology.…”

Section: Enteroendocrine Cells In Schizophreniamentioning

confidence: 99%

Involvement of Intestinal Enteroendocrine Cells in Neurological and Psychiatric Disorders

2022

Biomedicines

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Neurological and psychiatric patients have increased dramatically in number in the past few decades. However, effective treatments for these diseases and disorders are limited due to heterogeneous and unclear pathogenic mechanisms. Therefore, further exploration of the biological aspects of the disease, and the identification of novel targets to develop alternative treatment strategies, is urgently required. Systems-level investigations have indicated the potential involvement of the brain–gut axis and intestinal microbiota in the pathogenesis and regulation of neurological and psychiatric disorders. While intestinal microbiota is crucial for maintaining host physiology, some important sensory and regulatory cells in the host should not be overlooked. Intestinal epithelial enteroendocrine cells (EECs) residing in the epithelium throughout intestine are the key regulators orchestrating the communication along the brain-gut-microbiota axis. On one hand, EECs sense changes in luminal microorganisms via microbial metabolites; on the other hand, they communicate with host body systems via neuroendocrine molecules. Therefore, EECs are believed to play important roles in neurological and psychiatric disorders. This review highlights the involvement of EECs and subtype cells, via secretion of endocrine molecules, in the development and regulation of neurological and psychiatric disorders, including Parkinson’s disease (PD), schizophrenia, visceral pain, neuropathic pain, and depression. Moreover, the current paper summarizes the potential mechanism of EECs in contributing to disease pathogenesis. Examination of these mechanisms may inspire and lead to the development of new aspects of treatment strategies for neurological and psychiatric disorders in the future.

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“…In recent years, cross-tissue association analysis have been widely used in screening candidate susceptibility genes for complex multisystemic disorders whose biologically relevant tissues are not entirely clear, such as inflammatory bowel diseases, schizophrenia and Alzheimer’s disease. 16 17 …”

Section: Introductionmentioning

confidence: 99%

“…By imposing a group-lasso penalty on the effect sizes of single nucleotide polymorphisms (SNPs) across tissues, UTMOST encourages eQTL that are shared across tissues and keeps tissue-specific eQTL with strong effects. In recent years, cross-tissue association analysis have been widely used in screening candidate susceptibility genes for complex multisystemic disorders whose biologically relevant tissues are not entirely clear, such as inflammatory bowel diseases, schizophrenia and Alzheimer’s disease 16 17…”

Section: Introductionmentioning

confidence: 99%

Novel insight into the aetiology of rheumatoid arthritis gained by a cross-tissue transcriptome-wide association study

Wang

Yin

et al. 2022

RMD Open

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BackgroundAlthough genome-wide association studies (GWASs) have identified more than 100 loci associated with rheumatoid arthritis (RA) susceptibility, the causal genes and biological mechanisms remain largely unknown.MethodsA cross-tissue transcriptome-wide association study (TWAS) using the unified test for molecular signaturestool was performed to integrate GWAS summary statistics from 58 284 individuals (14 361 RA cases and 43 923 controls) with gene-expression matrix in the Genotype-Tissue Expression project. Subsequently, a single tissue by using FUSION software was conducted to validate the significant associations. We also compared the TWAS with different gene-based methodologies, including Summary Data Based Mendelian Randomization (SMR) and Multimarker Analysis of Genomic Annotation (MAGMA). Further in silico analyses (conditional and joint analysis, differential expression analysis and gene-set enrichment analysis) were used to deepen our understanding of genetic architecture and comorbidity aetiology of RA.ResultsWe identified a total of 47 significant candidate genes for RA in both cross-tissue and single-tissue test after multiple testing correction, of which 40 TWAS-identified genes were verified by SMR or MAGMA. Among them, 13 genes were situated outside of previously reported significant loci by RA GWAS. Both TWAS-based and MAGMA-based enrichment analyses illustrated the shared genetic determinants among autoimmune thyroid disease, asthma, type I diabetes mellitus and RA.ConclusionOur study unveils 13 new candidate genes whose predicted expression is associated with risk of RA, providing new insights into the underlying genetic architecture of RA.

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Cross-tissue transcriptome-wide association studies identify susceptibility genes shared between schizophrenia and inflammatory bowel disease

Cited by 19 publications

References 81 publications

Gastrointestinal and liver disease in patients with schizophrenia: A narrative review

Gastrointestinal and liver disease in patients with schizophrenia: A narrative review

Involvement of Intestinal Enteroendocrine Cells in Neurological and Psychiatric Disorders

Novel insight into the aetiology of rheumatoid arthritis gained by a cross-tissue transcriptome-wide association study

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